The present invention is for the use of 3-thiol, thioether, amino, alkylamino, or arylamino-benzo[b]thiophene-2-carboxamides, and 3-alkoxy, aryloxy, thiol, thioether, amino, alkylamino, or arylamino-benzofuran-2-carboxamides, and pharmaceutically acceptable salts thereof, to prevent the adhesion of leukocytes to endothelial cells. Leukocyte adherence to vascular endothelium is integral to the pathogenesis of inflammation. The adhesion process precedes transendothelial migration of leukocytes into surrounding tissue and ensuing tissue damage. Compounds that can block this initial adhesive interaction are expected to have efficacy in the treatment of inflammatory diseases such as rheumatoid arthritis, asthma, and psoriasis. Other indications would include, but are not limited to, adult respiratory distress syndrome, reperfusion injury, ischemia, ulcerative colitis, vasculitides, atherosclerosis, inflammatory bowel disease, and tumor metastases.
Adhesion receptors are organized into three main families: the selectins, the immunoglobulin superfamily, and the integrins [Nature 346, 426 (1990)]. Members of all three classes are involved in mediating leukocyte adhesion during inflammation [for reviews of this area see: Thrombosis and Hemostasis 65(3), 223 (1991); Clinical and Experimental Allergy 20, 619 (1990); Transplantation 48, 727 (1989); Biochemical Pharm. 40(8), 1683 (1990)]. Endothelial leukocyte adhesion molecule-1 (ELAM-1 or E-selectin) is a member of the selectin family of glycoproteins that promote cell-cell adhesion. ELAM-1 is reported to be maximally expressed on the surface of endothelial cells 4 hours after stimulation of the endothelial cells with cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor .alpha. (TNF-.alpha.) or other inflammatory mediators, such as lipopolysaccharide (LPS) [Pro. Nat. Acad. Sci. 84, 9238 (1987)].
Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin superfamily. It is also upregulated with maximum expression occurring 12 to 24 hours after stimulus. It has been shown that 4 hours after the endothelial cells are stimulated with an inflammatory mediator, both ELAM-1 and ICAM-1 are present on the cell surface [J. Clin. Invest. 82, 1746 (1988) and J. Immun. 137, 1893 (1986); Blood 78, 2721 (1991)].
The 3-thiol, thioether, amino, alkylamino, or arylamino-benzo[b]thiophene-2-carboxamides and 3-alkoxy, aryloxy, thiol, thioether, amino, alkylamino, or arylamino-benzofuran-2-carboxamides have been shown in an in vitro assay to prevent the adhesion of neutrophils to human umbilical vein endothelial cells (HUVECS) stimulated with TNF-.alpha.. In this assay, HUVECS are stimulated with TNF-.alpha. for 4 hours, after which the cells are assayed for their ability to adhere to human neutrophils labeled with either .sup.51 Cr or calcein, a fluorescent dye. The results obtained are shown in Tables 1-2. The details of this assay are described in the DETAILED DESCRIPTION.
Several of the 3-substituted-benzo[b]thiophene-2-carboxamides and 3-substituted-benzofuran-2-carboxamides contained here are included in the generic scope of U.S. Pat. No. 4,933,351, which claims these compounds as inhibitors of 5-lipoxygenase for the treatment of allergy, asthma, and inflammation, and/or in the generic scope of WO 9203-427 A, which claims these compounds as hypercalcaemic agents for the treatment of osteoporosis.
3-Alkoxy, aryloxy-, and arylalkyloxy-benzo[b]-thiophene-2-carboxamides are described in U.S. Pat. No. 5,208,253 as inhibitors of cell adhesion.
The present invention also relates to the above 3-substituted-benzo[b]thiophene- and benzofuran-2-carboxamides which inhibit the activation of human immunodeficiency virus (HIV), latent in infected mammals.
The pathogenesis of the human immunodeficiency virus (HIV) is complicated and as of yet not completely understood. The virus life cycle has theoretically been divided into afferent and efferent components. Virus binding, fusion, reverse transcription, and finally integration are among those events which encompass the afferent component of the life cycle. It is the afferent component of the HIV life cycle which is responsible for primary infection of HIV in an individual, generally followed by a burst of viraemia with or without clinical symptoms.
Many therapeutic strategies have been developed and targeted for intervention during the afferent events. See for example, Mitsuya H, Broder S. "Inhibition of the In Vitro Infectivity and Cytopathic Effect on Human T-Lymphotropic Virus Type III/Lymphadenopathy Virus-Associated Virus (HTLV-III/LAV) by 2',3'-Dideoxynucleosides." Proc. Natl. Acad. Sci (USA) 83, 1911-1915 (1986).
Whereas different stages of the afferent component offer the potential for effective therapeutic intervention, it has become increasingly apparent that intervention solely at these points is insufficient. After becoming infected with HIV and the disease progresses through the afferent stages, an individual experiences a prolonged period of clinical latency which may extend for several years and the individual remains in good health. At this point in time, low to absent levels of viraemia and virus replication in peripheral blood cells are achieved. At a later point, however, the disease eventually progresses to life-threatening immunosuppression (AIDS) for which there remains no cure. These later events are the clinical manifestations of the efferent stages of HIV infection.
The efferent component of the HIV life cycle includes those events necessary for the HIV provirus to successfully transcribe, translate, assemble, and produce virions. Onset of the events necessary for HIV-infected cells to progress from an asymptomatic, non-HIV expressive stage to a symptomatic, HIV expressive stage is referred to as activation. Presently, the efferent component and the cellular basis for activation is not completely understood. Nevertheless, if novel therapeutic agents and strategies are developed and implemented during the clinically asymptomatic phase to fight the progression toward AIDS, some hope may be afforded the estimated one million infected, but clinically asymptomatic individuals.
While the above 3-substituted-benzo[b]thiophene- and benzofuran-2-carboxamides have already generally been described, the present invention includes certain novel compounds and, more importantly, includes novel therapeutic uses for those already known compounds.